Pandemic influenza remains an important public liealth concern and a research priority for the Biodefense and Emerging Diseases program of NIAID. This is exemplified by the recent creation of six Centers of Excellence for Influenza Research and Surveillance (CEIRS) funded by NIAID. Although these centers cover important areas in influenza research, studies with the 1918 strain of influenza virus were excluded from these centers. This strain caused a severe pandemia in humans, with more than 40 million persons dying in the world. In 2004, we teamed up under a Program Project Grant an outstanding group of investigators with different expertises, ranging from structural biology to genetics, molecular biology, virology, molecular pathogenesis, animal models of disease, systems biology and biocontainment to better understand the biology of this virus strain. During the past 4 years of support we have sequenced and reconstructed from historical human tissues the 1918 virus. Our research has resulted in significant contributions that increased our knowledge on the structure, biology, host adaptation and pathogenesis of this virus. At the same time, we established novel animal models for studying influenza viruses, such as a non-human primate model of pathogenesis and vaccine efficacy, and a guinea pig model of transmission. Based on our previous studies, we now propose to continue to explore questions of relevance for pandemic influenza using the 1918 virus as a prototype human pandemic influenza virus: How influenza virus induces severe disease? What are the determinants of virulence of the 1918 virus? And of host tropism? How we can use humoral immunity to better prevent influenza virus disease? How host responses shape viral pathogenesis? We have kept the same team of investigators and added new co-PIs and core directors that expanded our previous expertise. We propose that by integrating multiple disciplines we will be able to address the scientific questions of this proposal, and therefore our team includes structural biologists, molecular biologists, virologists, immunologists, pathologists, systems biology experts and bioinformaticians. This integrated view of pandemic influenza virus biology fills a research gap not covered by the CEIRS.